1. Field of the Invention
The invention is directed to methods for the production and manufacture of vaccines for the treatment or prevention of infection due to Bordetella pertussis and, in particular, the invention is directed to a detoxified pertussis vaccine and methods for the administration of detoxified vaccines to patients.
2. Description of the Background
The bacterium Bordetella pertussis is the most common causative agent for the disease referred to as whooping cough. Whooping cough is a respiratory disease that can infect both adults and children. Although treatable with antibiotics, it can be a serious disease for infants especially. Clinically the disease is characterized by paroxysms of rapid coughs followed by inspiratory effort, often associated with a characteristic ‘whooping’ sound—thus the name. In more serious cases, there can be pneumonia and complications caused by pneumonia, and also brain oxygen deprivation which can lead to brain damage and death.
Although most often due to B. pertussis, about 5-10% of cases of whooping cough may be caused by a serologically related microorganism (e.g., B. parapertussis) (see, Mertsola (1985) Eur J Clin Microbiol 4; 123; Lautrop (1971) Lancet 1(7711) 1195-1198). Infections due to B. parapertussis are clinically mild as compared with B. pertussis and, due to the cross reactivity with B. pertussis makes B. parapertussis difficult to diagnose as the causative agent.
The first generation of vaccines against B. pertussis were whole cell vaccines (referred to as wP vaccines), composed of bacteria which were treated with chemicals such as formaldehyde to kill the cells and inactivate the toxic materials. Highly efficacious, these vaccines were introduced in many countries in the 1950s and 1960s. Although successful at reducing incidence of whooping cough, a major problem with wP vaccines was the high level of reactogenicity, which commonly included the side effect of fever and local reactions.
The need for a more defined vaccine was recognized which led to the development of a vaccine comprising lesser number of highly purified antigens from different microorganisms. The result was what was generally referred to as the component vaccine and contains immunogenic portions of diphtheria, tetanus and pertussis (DTP). Initial DTP vaccines contained pertussis endotoxin, surface lipooligosaccharide (LOS) of B. Pertussis (DTwP vaccines). LOS is a low molecular weight form of bacterial lipopolysaccharides (LPS). Although effective, these vaccines produced a number of deleterious side effects.
In the 1990's, newer pertussis vaccines were developed that, although less uniformly immunogenic, include only a few selected pertussis antigens, namely toxins and adhesins of B. pertussis. Although less defined as compared to component vaccines, these acellular vaccines (DTaP vaccines) are less likely to provoke side effects and have been approved by the FDA for administration to adults and children. Vaccines have been developed recently, also for administration to adults and children, which combine the tetanus and diphtheria toxoids with acellular pertussis vaccine. These (Tdap) vaccines, although less immunogenic than wP vaccines, contain reduced amounts of pertussis antigens compared to DTaP vaccines and, thus, have fewer side effects. Acellular vaccines containing purified B. pertussis proteins were less reactogenic and have been adopted for many vaccination programs around the world. Acellular vaccines typically containing pertussis toxin (PT), filamentous haemagglutinin (FHA) and quite often pertactin (PRN), are widely used and provide effective protection from the severity of whooping cough.
Despite vaccination, whooping cough remains an endemic disease (Mooi et al (2001) Emerging Infectious Diseases 7; 526), and has re-emerged in Australia, Canada and various areas of Europe; countries with highly vaccinated populations. A comparison of pre-vaccination strains with strains isolated from these areas has shown antigenic drift, particularly in PT and PRN (Mooi et al (1998) Infection and Immunity 66; 670). It has become accepted that current vaccinations protect against severe disease, but do not eliminate the B. pertussis infection (Cherry et al (1998) Vaccine 16; 1901, Hewlett and Halperin (1998) Vaccine 16; 1899, Storsaeter et al (1998) Vaccine 16; 1907). The defense mechanisms associated with B. pertussis allow the organism to escape the immunological processes that would otherwise destroy the microorganism.
Not surprisingly, vaccination using whole cell B. pertussis vaccines (Pw) have been shown to be protective against B. parapertussis infection as well, most likely due to an immunological similarity of the organisms. B. parapertussis infection in unvaccinated infants may lead to severe and fatal complications, whereas in individuals vaccinated with Pw, a milder, often subclinical course of whooping cough is seen (Long et al (1990) Pediatric Infect Dis J 9; 700). Thus, acellular pertussis vaccines containing only two or three purified proteins should reduce the ability of vaccination to protect against B. parapertussis. Further improved acellular vaccines against whooping cough are required that combine low reactogenicity with an ability to elicit a protective response against Bordetella, particularly with regard to infections of B. pertussis and B. parapertussis. 
Thus, a need currently exists for an effective pertussis vaccine that is uniformly immunogenic and protective against infection that has few or no side effects.